Developing High Performance Secure Multi-Party Computation Protocols in Healthcare: A Case Study of Patient Risk Stratification.

We demonstrate that secure multi-party computation (MPC) using garbled circuits is viable technology for solving clinical use cases that require cross-institution data exchange and collaboration. We describe two MPC protocols, based on Yao's garbled circuits and tested using large and realistically synthesized datasets. Linking records using private set intersection (PSI), we compute two metrics often used in patient risk stratification: high utilizer identification (PSI-HU) and comorbidity index calculation (PSI-CI). Cuckoo hashing enables our protocols to achieve extremely fast run times, with answers to clinically meaningful questions produced in minutes instead of hours. Also, our protocols are provably secure against any computationally bounded adversary in a semi-honest setting, the de-facto mode for cross-institution data analytics. Finally, these protocols eliminate the need for an implicitly trusted third-party "honest broker" to mediate the information linkage and exchange.

Toward a More Accurate Accrual to Clinical Trials: Joint Cohort Discovery Using Bloom Filters and Homomorphic Encryption.

Reliable cohort discovery is an essential early part of clinical study design. Indeed, it is the defining feature of many clinical research networks, including the recently launched Accrual to Clinical Trials (ACT) network. As currently deployed, however, the ACT network only allows cohort queries in isolated silos, rendering cohort discovery across sites unreliable. Here we demonstrate a novel protocol to provide network participants access to more accurate combined cohort estimates (union cardinality) with other sites. A two-party Elgamal protocol is implemented to ensure privacy and security imperatives, and a special attribute of Bloom filters is exploited for accurate and fast cardinality estimates. To emulate mandatory privacy protecting obfuscation factors (like those applied to the counts reported for individual sites by ACT), we configure the Bloom filter based on the individual site cohort sizes, striking an appropriate balance between accuracy and privacy. Finally, we discuss additional approval and data governance steps required to incorporate our protocol in the current ACT infrastructure.

Preventing dysbiosis of the neonatal mouse intestinal microbiome protects against late-onset sepsis.

Late-onset sepsis (LOS) is thought to result from systemic spread of commensal microbes from the intestines of premature infants. Clinical use of probiotics for LOS prophylaxis has varied owing to limited efficacy, reflecting an incomplete understanding of relationships between development of the intestinal microbiome, neonatal dysbiosis and LOS. Using a model of LOS, we found that components of the developing microbiome were both necessary and sufficient to prevent LOS. Maternal antibiotic exposure that eradicated or enriched transmission of Lactobacillus murinus exacerbated and prevented disease, respectively. Prophylactic administration of some, but not all Lactobacillus spp. was protective, as was administration of Escherichia coli. Intestinal oxygen level was a major driver of colonization dynamics, albeit via mechanisms distinct from those in adults. These results establish a link between neonatal dysbiosis and LOS, and provide a basis for rational selection of probiotics that modulate primary succession of the microbiome to prevent disease.

Enabling Privacy Preserving Record Linkage Systems Using Asymmetric Key Cryptography.

We present a systemic approach to devise and deploy Privacy Preserving Record Linkage (PPRL) systems using asymmetric key cryptography and illustrate the strengths of such an approach. With our approach, the security implications of sharing a common secret salt across the network may be avoided, allowing the local participating sites to use private keys along with the current cryptographic hashes to maximally secure their own data. In addition, the final cyphertext tokens are compatible with those used by existing record linkage modules, allowing seamless integration with the existing PPRL infrastructures for downstream analysis. Finally, study-specific hash production requires action only by the central party. The main intuition for this work is derived from how asymmetric key approaches have enabled internet-scale applications. We demonstrate that such a design, where the local sites no longer need special-purpose software, affords greater flexibility and scalability for large scale multi-site linkage studies.

Effect of fluconazole prophylaxis on candidiasis and mortality in premature infants: a randomized clinical trial.

IMPORTANCE: Invasive candidiasis in premature infants causes death and neurodevelopmental impairment. Fluconazole prophylaxis reduces candidiasis, but its effect on mortality and the safety of fluconazole are unknown. OBJECTIVE: To evaluate the efficacy and safety of fluconazole in preventing death or invasive candidiasis in extremely low-birth-weight infants. DESIGN, SETTING, AND PATIENTS: This study was a randomized, blinded, placebo-controlled trial of fluconazole in premature infants. Infants weighing less than 750 g at birth (N = 361) from 32 neonatal intensive care units (NICUs) in the United States were randomly assigned to receive either fluconazole or placebo twice weekly for 42 days. Surviving infants were evaluated at 18 to 22 months corrected age for neurodevelopmental outcomes. The study was conducted between November 2008 and February 2013. INTERVENTIONS: Fluconazole (6 mg/kg of body weight) or placebo. MAIN OUTCOMES AND MEASURES: The primary end point was a composite of death or definite or probable invasive candidiasis prior to study day 49 (1 week after completion of study drug). Secondary and safety outcomes included invasive candidiasis, liver function, bacterial infection, length of stay, intracranial hemorrhage, periventricular leukomalacia, chronic lung disease, patent ductus arteriosus requiring surgery, retinopathy of prematurity requiring surgery, necrotizing enterocolitis, spontaneous intestinal perforation, and neurodevelopmental outcomes-defined as a Bayley-III cognition composite score of less than 70, blindness, deafness, or cerebral palsy at 18 to 22 months corrected age. RESULTS: Among infants receiving fluconazole, the composite primary end point of death or invasive candidiasis was 16% (95% CI, 11%-22%) vs 21% in the placebo group (95% CI, 15%-28%; odds ratio, 0.73 [95% CI, 0.43-1.23]; P = .24; treatment difference, -5% [95% CI, -13% to 3%]). Invasive candidiasis occurred less frequently in the fluconazole group (3% [95% CI, 1%-6%]) vs the placebo group (9% [95% CI, 5%-14%]; P = .02; treatment difference, -6% [95% CI, -11% to -1%]). The cumulative incidences of other secondary outcomes were not statistically different between groups. Neurodevelopmental impairment did not differ between the groups (fluconazole, 31% [95% CI, 21%-41%] vs placebo, 27% [95% CI, 18%-37%]; P = .60; treatment difference, 4% [95% CI, -10% to 17%]). CONCLUSIONS AND RELEVANCE: Among infants with a birth weight of less than 750 g, 42 days of fluconazole prophylaxis compared with placebo did not result in a lower incidence of the composite of death or invasive candidiasis. These findings do not support the universal use of prophylactic fluconazole in extremely low-birth-weight infants. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00734539.

Incidence and impact of CMV infection in very low birth weight infants.

BACKGROUND AND OBJECTIVES: Congenital cytomegalovirus (CMV) is the leading cause of nongenetic deafness in children in the United States and can cause neurodevelopmental impairment in term infants. Limited data exist regarding congenital CMV infections in preterm infants. We aimed to determine the incidence and association with outcomes of congenital CMV in very low birth weight (VLBW) preterm infants. METHODS: VLBW infants born in 1993 to 2008 and admitted to the University of Alabama in Birmingham Regional Neonatal ICU were screened on admission for congenital CMV. CMV status and clinical outcomes were identified by using internal patient databases and hospital-based medical records. The primary outcome was death. Secondary outcomes included evidence of neurologic injury in the form of abnormal cranial ultrasound findings, sensorineural hearing loss, or abnormal motor development. Multivariate analysis was performed. RESULTS: Eighteen of 4594 VLBW infants had congenital CMV (0.39%; 95% confidence interval, 0.25%-0.62%). An additional 16 infants (0.35%; 95% confidence interval, 0.21%-0.57%) were identified who acquired CMV postnatally. Congenital CMV was not associated with death. Compared with controls, congenitally infected VLBW infants were more likely to have hearing loss at initial screening (67% vs. 9%, P < .0001) and confirmed at follow-up (83% vs. 2.1%, P < .0001). Congenital CMV was also associated with abnormal neuroimaging (72% vs. 25%, P < .0001) and adverse developmental motor outcomes (43% vs. 9%, P = .02). Acquired CMV was not associated with any adverse outcomes. CONCLUSIONS: Congenital CMV in VLBW infants is associated with high rates of neurologic injury and hearing loss but not death.

Outcomes of extremely low birthweight infants with acidosis at birth.

OBJECTIVES: To test the hypothesis that acidosis at birth is associated with the combined primary outcome of death or neurodevelopmental impairment (NDI) in extremely low birthweight (ELBW) infants, and to develop a predictive model of death/NDI exploring perinatal acidosis as a predictor variable. STUDY DESIGN: The study population consisted of ELBW infants born between 2002 and 2007 at National Institute of Child Health and Development (NICHD) Neonatal Research Network hospitals. Infants with cord blood gas data and documentation of either mortality prior to discharge or 18-22 month neurodevelopmental outcomes were included. Multiple logistic regression analysis was used to determine the contribution of perinatal acidosis, defined as a cord blood gas with a pH<7 or base excess (BE) <-12, to death/NDI in ELBW infants. In addition, a multivariable model predicting death/NDI was developed. RESULTS: 3979 patients were identified of whom 249 had a cord gas pH<7 or BE<-12 mEq/L. 2124 patients (53%) had the primary outcome of death/NDI. After adjustment for confounding variables, pH<7 and BE<-12 mEq/L were each significantly associated with death/NDI (OR=2.5 (1.6, 4.2) and OR=1.5 (1.1, 2.0), respectively). However, inclusion of pH or BE did not improve the ability of the multivariable model to predict death/NDI. CONCLUSIONS: Perinatal acidosis is significantly associated with death/NDI in ELBW infants. Perinatal acidosis is infrequent in ELBW infants, however, and other factors are more important in predicting death/NDI.

Allogeneic Th1 cells home to host bone marrow and spleen and mediate IFNγ-dependent aplasia.

Bone marrow graft failure and poor graft function are frequent complications after hematopoietic stem cell transplantation and result in significant morbidity and mortality. Both conditions are associated with graft-versus-host disease (GVHD), although the mechanism remains undefined. Here we show, in 2 distinct murine models of GVHD (complete MHC- and class II-disparate) that mimic human peripheral blood stem cell transplantation, that Th1 CD4(+) cells induce bone marrow failure in allogeneic recipients. Bone marrow failure after transplantation of allogeneic naïve CD4(+) T cells was associated with increased CD4(+) Th1 cell development within bone marrow and lymphoid tissues. Using IFNγ-reporter mice, we found that Th1 cells generated during GVHD induced bone marrow failure after transfers into secondary recipients. Homing studies demonstrated that transferred Th1 cells express CXCR4, which was associated with accumulation within bone marrow and spleen. Allogeneic Th1 cells were activated by radiation-resistant host bone marrow cells and induced bone marrow failure through an IFNγ-dependent mechanism. Thus, allogeneic Th1 CD4(+) cells generated during GVHD traffic to hematopoietic sites and induce bone marrow failure via IFNγ-mediated toxicity. These results have important implications for prevention and treatment of bone marrow graft failure after hematopoietic stem cell transplantation.

Retinoic acid hypersensitivity promotes peripheral tolerance in recent thymic emigrants.

Whereas thymic education eliminates most self-reactive T cells, additional mechanisms to promote tolerance in the periphery are critical to prevent excessive immune responses against benign environmental Ags and some self-Ags. In this study we show that murine CD4(+) recent thymic emigrants (RTEs) are programmed to facilitate tolerance in the periphery. Both in vitro and in vivo, naive RTEs more readily upregulate Foxp3 than do mature naive cells after stimulation under tolerogenic conditions. In RTEs, a relatively high sensitivity to retinoic acid contributes to decreased IFN-γ production, permitting the expression of Foxp3. Conversely, mature naive CD4 cells have a lower sensitivity to retinoic acid, resulting in increased IFN-γ production and subsequent IFN-γ-mediated silencing of Foxp3 expression. Enhanced retinoic acid signaling and Foxp3 induction in RTEs upon Ag encounter in the periphery may serve as form of secondary education that complements thymic education and helps avoid inappropriate immune responses. This mechanism for tolerance may be particularly important in settings where RTEs comprise a large fraction of the peripheral T cell pool, such as in newborns or after umbilical cord blood transplant.

Safety and effectiveness of meropenem in infants with suspected or complicated intra-abdominal infections.

BACKGROUND: Intra-abdominal infections are common in young infants and lead to significant morbidity and mortality. Meropenem is a broad-spectrum antimicrobial with excellent activity against pathogens associated with intra-abdominal infections. The purpose of this study was to determine the safety and effectiveness of meropenem in young infants with suspected or complicated intra-abdominal infections. METHODS: Preterm and term infants <91 days of age with suspected or confirmed intra-abdominal infections hospitalized in 24 neonatal intensive care units were studied in an open-label, multiple-dose study. Adverse events and serious adverse events were collected through 3 and 30 days following the last meropenem dose, respectively. Effectiveness was assessed by 3 criteria: death, bacterial cultures, and presumptive clinical cure score. RESULTS: Of 200 subjects enrolled in the study, 99 (50%) experienced an adverse event, and 34 (17%) had serious adverse events; no adverse events were probably or definitely related to meropenem. The most commonly reported adverse events were sepsis (6%), seizures (5%), elevated conjugated bilirubin (5%), and hypokalemia (5%). Only 2 of the serious adverse events were determined to be possibly related to meropenem (isolated ileal perforation and an episode of fungal sepsis). Effectiveness was evaluable in 192 (96%) subjects, and overall treatment success was 84%. CONCLUSIONS: Meropenem was well tolerated in this cohort of critically ill infants, and the majority of infants treated with meropenem met the definition of therapeutic success. CLINICAL TRIALS REGISTRATION: NCT00621192.

Developmental regulation of Th17-cell capacity in human neonates.

Human neonates are at significantly greater risk of serious infection than immunocompetent adults. In particular, very low birth weight infants in the neonatal intensive care nursery are at high risk of developing life-threatening bacterial and fungal infections. Recent studies have identified Th17 cells as critical mediators of immunity to bacterial and fungal infections at epithelial barriers. Little is known, however, about the ontogeny of Th17-cell responses in humans. The frequency of serious bacterial infections in preterm infants and the importance of Th17 cells in providing protection against such infections in animal studies prompted us to study Th17-cell development in human neonates. Naïve CD4(+) T cells from extremely preterm infants, term infants, and adults were assayed for their capacity to develop into Th17 effector cells. Surprisingly, Th17-cell capacity was inversely related to developmental age. Neonates expressed higher levels of IL-23R, RORγt, and STAT3 prior to activation and showed a significant Th17-cell bias after activation. In contrast, adult cells expressed more TBX21 with a corresponding Th1-cell bias. CD161 expression on Th17-cell precursors was also developmentally regulated. Our results suggest there is significant developmental regulation of CD4(+) effector lineages with a strong bias toward Th17-cell development early in life.

Epithelial cells in fetal intestine produce chemerin to recruit macrophages.

Macrophages are first seen in the fetal intestine at 11-12 wk and rapidly increase in number during the 12- to 22-wk period of gestation. The development of macrophage populations in the fetal intestine precedes the appearance of lymphocytes and neutrophils and does not require the presence of dietary or microbial antigens. In this study, we investigated the role of chemerin, a recently discovered, relatively selective chemoattractant for macrophages, in the recruitment of macrophage precursors to the fetal intestine. Chemerin mRNA/protein expression was measured in jejunoileal tissue from 10- to 24-wk human fetuses, neonates operated for intestinal obstruction, and adults undergoing bariatric surgery. The expression of chemerin in intestinal epithelial cells (IECs) was confirmed by using cultured primary IECs and IEC-like cell lines in vitro. The regulatory mechanisms involved in chemerin expression were investigated by in silico and immunolocalization techniques. IECs in the fetal, but not mature, intestine express chemerin. Chemerin expression peaked in the fetal intestine at 20-24 wk and then decreased to original low levels by full term. During the 10- to 24-wk period, chemerin accounted for most of the macrophage chemotactic activity of cultured fetal IECs. The maturational changes in chemerin expression correlated with the expression of retinoic acid receptor-beta in the intestine. Chemerin is an important mediator of epithelial-macrophage cross talk in the fetal/premature, but not in the mature, intestine. Understanding the regulation of the gut macrophage pool is an important step in development of novel strategies to boost mucosal immunity in premature infants and other patient populations at risk of microbial translocation.

Developmental changes in circulating IL-8/CXCL8 isoforms in neonates.

Interleukin-8 (IL-8/CXCL8) is widely expressed in fetal tissues although inflammatory changes are not seen. Circulating IL-8 is comprised of an endothelial-derived [ala-IL-8](77) isoform and another, more potent [ser-IL-8](72) secreted by most other cells; [ala-IL-8](77) can be converted into [ser-IL-8](72) by proteolytic removal of an N-terminal pentapeptide from [ala-IL-8](77). In this study, we show [ala-IL-8](77) is the predominant circulating isoform of IL-8 in premature neonates but not in term neonates/adults, who have [ser-IL-8](72) as the major isoform. This isoform switch from the less potent [ala-IL-8](77) to [ser-IL-8](72) correlates with a maturational increase in the neutrophil chemotactic potency of plasma IL-8. The emergence of [ser-IL-8](72) as the major isoform is likely due to increased plasma [ala-IL-8](77)-convertase activity and/or changes in the cellular sources of IL-8. Developmental changes in IL-8 isoforms may serve to minimize its inflammatory effects in the fetus and also provide a mechanism to restore its full activity after birth.

MutationFinder: a high-performance system for extracting point mutation mentions from text.

Discussion of point mutations is ubiquitous in biomedical literature, and manually compiling databases or literature on mutations in specific genes or proteins is tedious. We present an open-source, rule-based system, MutationFinder, for extracting point mutation mentions from text. On blind test data, it achieves nearly perfect precision and a markedly improved recall over a baseline. AVAILABILITY: MutationFinder, along with a high-quality gold standard data set, and a scoring script for mutation extraction systems have been made publicly available. Implementations, source code and unit tests are available in Python, Perl and Java. MutationFinder can be used as a stand-alone script, or imported by other applications. PROJECT URL: http://bionlp.sourceforge.net.

Rapid pattern development for concept recognition systems: application to point mutations.

The primary biomedical literature is being generated at an unprecedented rate, and researchers cannot keep abreast of new developments in their fields. Biomedical natural language processing is being developed to address this issue, but building reliable systems often requires many expert-hours. We present an approach for automatically developing collections of regular expressions to drive high-performance concept recognition systems with minimal human interaction. We applied our approach to develop MutationFinder, a system for automatically extracting mentions of point mutations from the text. MutationFinder achieves performance equivalent to or better than manually developed mutation recognition systems, but the generation of its 759 patterns has required only 5.5 expert-hours. We also discuss the development and evaluation of our recently published high-quality, human-annotated gold standard corpus, which contains 1,515 complete point mutation mentions annotated in 813 abstracts. Both MutationFinder and the complete corpus are publicly available at (http://mutationfinder.sourceforge.net/).

Cd4+Cd25+ regulatory T cells and their therapeutic potential.

The human immune system mounts specific responses to a vast array of antigens. Although this is clearly beneficial in fighting off harmful infections and cancerous cells, the system must be carefully controlled to ensure that normal self-antigens are not targeted. A recently characterized subset of T cells, identified by their cell surface expression of CD4 and CD25, is critical in regulating the function of other immune cells and preventing potentially harmful autoimmune responses. This article reviews what is currently known about these so-called regulatory T cells and discusses the therapeutic potential of these cells to modulate human immune-based diseases.

Antigen-nonspecific recruitment of Th2 cells to the lung as a mechanism for viral infection-induced allergic asthma.

Respiratory viral infections have been shown to trigger exacerbations of asthma; however, the mechanism by which viral Th1-type inflammation exacerbates an allergic Th2-type disease remains unclear. We have previously shown that although adoptively transferred Th2 cells are inefficiently recruited to the lung in response to Ag, cotransfer of Th1 cells can increase accumulation of Th2 cells. In this study, we show that respiratory viral infection increases recruitment of resting Th2 cells specific for OVA even in the absence of OVA challenge. These findings suggest that the mechanism by which Th1-type inflammation enhances allergy is via an effect on recruitment. To study the role of the antigenic specificity of Th1 cells in the enhancement of Th2 cell recruitment and to determine whether virus-induced recruitment of OVA-specific Th2 cells may involve Th1 cells specific to a different Ag, we tested whether hen egg lysozyme-specific Th1 cells could synergize with OVA-specific Th2 cells. Challenge of mice that had received adoptively transferred Th1 cells plus Th2 cells induced the expression of inflammatory chemokines in the lung and increased both recruitment and activation of Th2 cells, leading to eosinophil recruitment, even in the absence of challenge with the Th2 Ag. Interestingly, as IL-5 supports eosinophilia, culture of resting Th2 cells with fresh APC induced production of IL-5 in the absence of specific Ag. Thus, Ag-specific activation of Th1 cells enhances the recruitment potential of the lung leading to recruitment and activation of Th2 cells. This implies that circulating Th2 cells in allergic individuals could enter the lungs in response to infection or inflammation and become activated to trigger allergy.

Nonhematopoietic expression of Janus kinase 3 is required for efficient recruitment of Th2 lymphocytes and eosinophils in OVA-induced airway inflammation.

Tyrosine kinases of the Janus kinase (Jak) family transduce signals from the type I and type II cytokine receptors. Jak3 is unique in this family because its expression must be induced and is predominantly limited to cells of the lymphoid and myeloid lineages. Deficient expression of Jak3 interferes with normal development and function of T, B, and NK cells. Using irradiated Jak3-deficient (Jak3-/-) mice reconstituted with normal bone marrow (Jak3-/-chimeric mice), we have investigated possible actions of Jak3 outside of the hematopoietic system. We show that efficient recruitment of inflammatory cells to the airways of OVA-sensitized mice challenged with aerosolized OVA requires the expression of Jak3 in radioresistant nonhematopoietic cells. Failure to develop eosinophil-predominant airway inflammation in Jak3-/- chimeric mice is not due to failure of T cell sensitization, because Jak3-/- chimeric mice showed delayed-type hypersensitivity responses indistinguishable from wild-type chimeric mice. Jak3-/- chimeric mice, however, express less endothelial-associated VCAM-1 after airway Ag challenge. Given the key role of VCAM-1 in recruitment of Th2 cells and eosinophils, our data suggest that Jak3 in airway-associated endothelial cells is required for the expression of eosinophilic airway inflammation. This requirement for nonhematopoietic expression of Jak3 represents the first demonstration of a physiological function of Jak3 outside of the lymphoid lineages.